Abstract

Background: The androgen receptor (AR) and PI3K/AKT/mTOR signaling axis are two key pathways that are activated in prostate cancer (PC). Although interference with the AR axis is the common first-line treatment for controlling metastatic recurrent PC, fast-growing PC progresses rapidly on hormone therapy and chemotherapy to a terminal condition within 18 to 24 months. Inhibitors of the PI3K/AKT/mTOR axis, such as rapamycin and the dual inhibitor BEZ-235 (Novartis), are ineffective in treating metastatic PC in part due to feedback regulations that activate the AR axis. Reciprocally, inhibition of AR activity reduces the expression of an AKT phosphatase, which is an AR target gene, with consequent increase of the AKT kinase activity. The antibiotic salinomycin, a product of the bacterium Streptomyces albus, has known anti-neoplastic activity, and in a screen of 16,000 small molecules, salinomycin was found to be the most potent in causing apoptosis of breast cancer stem cells. We previously reported that salinomycin treatment elevated intracellular oxidative stress and induced growth arrest of PC cells due to apoptosis.

Design and Results: Here we report further elaboration of the underlying mechanism for growth arrest of androgen-dependent (LNCaP) and castration-resistant (C4-2B) human prostate cancer cells by salinomycin at sub-micromolar concentrations. We report that salinomycin can significantly reduce mTOR activity in both LNCaP and C4-2B cells without altering the mTOR activity of non-malignant RWPE-1 prostate epithelial cells. The specificity of the salinomycin effect is evidenced by the result that other anti-cancer agents such as docetaxel, the plant lignan deoxypodophyllotoxin and vitamin D did not alter mTOR activity. Preliminary results suggest that salinomycin may also induce autophagy in PC cells. Importantly, AR expression was markedly reduced in salinomycin-treated prostate cancer cells, suggesting dual targeting of the AR pathway and PI3K/AKT/mTOR axis by this antibiotic.

Conclusion: We conclude that salinomycin targets two pivotal pathways that promote prostate cancer progression. Unlike other PI3K/AKT/mTOR inhibitors, the AR-activating feedback cross regulation did not compromise the therapeutic potential of salinomycin. Salinomycin-targeted interventions of the survival signals for castration-resistant PC will further avoid chemotherapy-induced toxicity. Preclinical validation of our results will pave the way for testing the efficacy of salinomycin against prostate cancer in a clinical setting.

Supported by a Merit-Review grant from the Department of Veterans Affairs.